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Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2

Anje Cauwels (UGent) , Ben Janssen, Anouk Waeytens (UGent) , Claude Cuvelier (UGent) and Peter Brouckaert (UGent)
(2003) NATURE IMMUNOLOGY. 4(4). p.387-393
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Abstract
Dysregulated apoptotic cell death contributes to many pathological conditions, including sepsis, prompting the suggestion that caspase inhibition to block apoptosis could have useful therapeutic applications. Because the cytokine tumor necrosis factor (TNF, also known as TNF-alpha) is both proapoptotic and pro-inflammatory and is involved in septic shock, we tested whether caspase inhibition would alleviate TNF-induced toxicity in vivo. General caspase inhibition by the protease inhibitor zVAD-fmk exacerbated TNF toxicity by enhancing oxidative stress and mitochondrial damage, resulting in hyperacute hemodynamic collapse, kidney failure and death. Thus, survival of TNF toxicity depends on caspase-dependent processes. Our results demonstrated the pathophysiological relevance of caspase-independent, ROS-mediated pathways in response to lethal TNF-induced shock in mice. In addition, survival of TNF toxicity seemed to require a caspase-dependent protective feedback on excessive reactive oxygen species (ROS) formation and phospholipase A2 activation.
Keywords
ACTIVATION, MICE, CELL APOPTOSIS, TNF-ALPHA, FAS, SIGNAL-TRANSDUCTION, DEATH DOMAIN, INDUCED ENTEROCYTE APOPTOSIS, DOMAIN KINASE RIP, ARACHIDONIC-ACID RELEASE

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Chicago
Cauwels, Anje, Ben Janssen, Anouk Waeytens, Claude Cuvelier, and Peter Brouckaert. 2003. “Caspase Inhibition Causes Hyperacute Tumor Necrosis Factor-induced Shock via Oxidative Stress and Phospholipase A2.” Nature Immunology 4 (4): 387–393.
APA
Cauwels, Anje, Janssen, B., Waeytens, A., Cuvelier, C., & Brouckaert, P. (2003). Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. NATURE IMMUNOLOGY, 4(4), 387–393.
Vancouver
1.
Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P. Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. NATURE IMMUNOLOGY. 2003;4(4):387–93.
MLA
Cauwels, Anje, Ben Janssen, Anouk Waeytens, et al. “Caspase Inhibition Causes Hyperacute Tumor Necrosis Factor-induced Shock via Oxidative Stress and Phospholipase A2.” NATURE IMMUNOLOGY 4.4 (2003): 387–393. Print.
@article{1087229,
  abstract     = {Dysregulated apoptotic cell death contributes to many pathological conditions, including sepsis, prompting the suggestion that caspase inhibition to block apoptosis could have useful therapeutic applications. Because the cytokine tumor necrosis factor (TNF, also known as TNF-alpha) is both proapoptotic and pro-inflammatory and is involved in septic shock, we tested whether caspase inhibition would alleviate TNF-induced toxicity in vivo. General caspase inhibition by the protease inhibitor zVAD-fmk exacerbated TNF toxicity by enhancing oxidative stress and mitochondrial damage, resulting in hyperacute hemodynamic collapse, kidney failure and death. Thus, survival of TNF toxicity depends on caspase-dependent processes. Our results demonstrated the pathophysiological relevance of caspase-independent, ROS-mediated pathways in response to lethal TNF-induced shock in mice. In addition, survival of TNF toxicity seemed to require a caspase-dependent protective feedback on excessive reactive oxygen species (ROS) formation and phospholipase A2 activation.},
  author       = {Cauwels, Anje and Janssen, Ben and Waeytens, Anouk and Cuvelier, Claude and Brouckaert, Peter},
  issn         = {1529-2908},
  journal      = {NATURE IMMUNOLOGY},
  keyword      = {ACTIVATION,MICE,CELL APOPTOSIS,TNF-ALPHA,FAS,SIGNAL-TRANSDUCTION,DEATH DOMAIN,INDUCED ENTEROCYTE APOPTOSIS,DOMAIN KINASE RIP,ARACHIDONIC-ACID RELEASE},
  language     = {eng},
  number       = {4},
  pages        = {387--393},
  title        = {Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2},
  url          = {http://dx.doi.org/10.1038/ni914},
  volume       = {4},
  year         = {2003},
}

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